Abstract
This study aimed to determine the role of dexmedetomidine (Dex) in neuropathic pain (NP) after chronic constriction injury (CCI) in a rat model as well as its underlying mechanism. First, a CCI rat model was established. After treatment with Dex, the severity of NP was ascertained by monitoring paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at different time points. Immunohistochemical analysis was performed to determine the levels of Keap1 and Nrf2 in the spinal cord. Furthermore, the levels of Keap1–Nrf2–HO-1 pathway molecules, apoptotic proteins, and antioxidant genes in the spinal cord or isolated primary microglia were determined using quantitative polymerase chain reaction and western blotting. The release of proinflammatory cytokines was detected via enzyme-linked immunosorbent assay. To evaluate Dex-treated CCI-induced NP via the Keap1–Nrf2–HO-1 pathway, the rats were intrathecally injected with lentivirus to upregulate or downregulate the expression of Keap1. We found that Dex inhibited pathological changes and alleviated sciatic nerve pain as well as repressed inflammation, apoptosis, and redox disorders of the spinal cord in CCI rats. Keap1 protein expression was substantially downregulated, whereas Nrf2 and HO-1 expressions were significantly upregulated in the spinal cord after Dex administration. Additionally, Keap1 overexpression counteracted Dex-mediated inhibition of NP. Keap1 overexpression led to a decrease in Nrf2 and HO-1 levels as well as PWT and PWL but led to an aggravation of inflammation and antioxidant disorders and increased apoptosis. Keap1 silencing alleviated NP in rats with CCI, as evidenced by an increase in PWT and PWL. Keap1 depletion resulted in the alleviation of inflammation and spinal cord tissue injury in CCI rats. Collectively, these findings suggest that Dex inhibits the Keap1–Nrf2–HO-1-related antioxidant response, inflammation, and apoptosis, thereby alleviating NP in CCI rats.
Highlights
Neuropathic pain (NP), which is chronic pain that arises as a direct consequence of a health condition or a disease damaging the somatosensory system (Popiolek-Barczyk and Mika, 2016), has a complex etiological mechanism and insufficient clinical outcome
The results showed that these three inflammatory factors were robustly produced in the constriction injury (CCI) group, whereas Dex treatment obviously inhibited their expression (Figure 1C). quantitative polymerase chain reaction (qPCR) and Western blotting (WB) were performed to determine the expressions of the pro-apoptotic factors caspase-9, Bax, and Bak
Dex-treated rats were less sensitive to mechanical and thermal stimulation and showed high activation of the Kelchlike ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2–related factor 2 (Nrf2) signaling axis compared with CCI rats
Summary
Neuropathic pain (NP), which is chronic pain that arises as a direct consequence of a health condition or a disease damaging the somatosensory system (Popiolek-Barczyk and Mika, 2016), has a complex etiological mechanism and insufficient clinical outcome. Dexmedetomidine (Dex) is a highly selective, sedative, anxiolytic, and analgesic α2-adrenergic agonist with minimal effect on respiration (Cortinez et al, 2004; Hsu et al, 2004). It has widespread application in patients admitted to intensive care units, special populations with respiratory disorders, and pediatric patients (Carollo et al, 2008; Jakob et al, 2014). Previous studies reported that Dex alleviates chronic constriction injury (CCI)induced NP by mediating the Toll-like receptor 4 (TLR4)– nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) (Zhao et al, 2020), mitogen-activated protein kinase (MAPK)–extracellular signal-regulated kinase (ERK) (Lin et al, 2018), and Janus kinase (JAK)–signal transducer and activator of transcription (STAT) (Xun and Zheng, 2020) signaling axes. We explored the involvement of the Kelchlike ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2–related factor 2 (Nrf2) pathway in Dex-ameliorated NP
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